Liver transplantation provides life saving treatment for patients with end-stage liver disease. However, the potential of this therapy is limited by an inadequate supply of deceased donor livers to treat all those who could benefit. This has resulted in narrow indications for liver transplantation, high waiting list mortality, and increased use of marginal organs that worsen post transplant survival rates and increase costs. We believe that pretransplant ex vivo donor liver perfusion (EVLP) has unparalled potential to alter this paradigm. Unlike the current standard liver preservation by static cold storage (SCS) in which incompletely arrested metabolic activity under anoxic conditions leads to gradual exhaustion of cellular energy stores and progressive deterioration of graft quality, under EVLP, cellular aerobic respiration is restored by oxygenated perfusion allowing normal metabolic processes to ensue ex vivo. This will permit pretransplant recovery for grafts injured by warm ischemia (such as those from DCD donors), diagnosis of grafts suitable from those nonsuitable for transplant and a marked net expansion of the organ pool for transplantation. In this proposed project, we seek to define the most appropriate and effective application of EVLP to liver transplants. We will investigate the boundaries of organ injury that allows recovery by EVLP and will delineate the ideal parameters of liver perfusion. These studies will also provide a wealth of data to inform future designed to identify multi parameter discriminators of organ suitability for transplantation. In the final aim of of this project, we utilize the information gained in Aims I and II to conduct a randomized comparison of SCS and EVLP using DCD livers as a prelude to a clinical trial. Collectively, these studies will generate data critically necessary in optimal development of the field of ex vivo liver perfusion.